4-6301089-C-G

Position:

chr4-6301089-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_StrongBP6BS2

The NM_006005.3(WFS1):c.1294C>G(p.Leu432Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,614,054 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L432Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 20 hom. )

Consequence

WFS1
NM_006005.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:15

Conservation

PhyloP100: 1.74

Variant links:

Genes affected

WFS1 (HGNC:12762): (wolframin ER transmembrane glycoprotein) This gene encodes a transmembrane protein, which is located primarily in the endoplasmic reticulum and ubiquitously expressed with highest levels in brain, pancreas, heart, and insulinoma beta-cell lines. Mutations in this gene are associated with Wolfram syndrome, also called DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness), an autosomal recessive disorder. The disease affects the brain and central nervous system. Mutations in this gene can also cause autosomal dominant deafness 6 (DFNA6), also known as DFNA14 or DFNA38. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Mar 2009]

WFS1 links:

WFS1 (HGNC:):

WFS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity WFS1_HUMAN there are 13 pathogenic changes around while only 4 benign (76%) in NM_006005.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-6301090-T-A is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.03004542).

BP6

Variant 4-6301089-C-G is Benign according to our data. Variant chr4-6301089-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=7}. Variant chr4-6301089-C-G is described in Lovd as [Benign]. Variant chr4-6301089-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
WFS1	NM_006005.3 linkuse as main transcript	c.1294C>G	p.Leu432Val	missense_variant	8/8	ENST00000226760.5	NP_005996.2	O76024A0A0S2Z4V6
WFS1	NM_001145853.1 linkuse as main transcript	c.1294C>G	p.Leu432Val	missense_variant	8/8		NP_001139325.1	O76024A0A0S2Z4V6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
WFS1	ENST00000226760.5 linkuse as main transcript	c.1294C>G	p.Leu432Val	missense_variant	8/8	1	NM_006005.3	ENSP00000226760.1		O76024

Frequencies

GnomAD3 genomes

AF:

0.00312

AC:

475

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00426

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00390

AC:

981

AN:

251294

Hom.:

AF XY:

0.00405

AC XY:

550

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00439

Gnomad ASJ exome

AF:

0.0160

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00189

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.00488

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00381

AC:

5566

AN:

1461746

Hom.:

Cov.:

103

AF XY:

0.00381

AC XY:

2771

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00440

Gnomad4 ASJ exome

AF:

0.0148

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00201

Gnomad4 FIN exome

AF:

0.000357

Gnomad4 NFE exome

AF:

0.00393

Gnomad4 OTH exome

AF:

0.00503

GnomAD4 genome

AF:

0.00311

AC:

474

AN:

152308

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

233

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00438

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000831

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00426

Gnomad4 OTH

AF:

0.00993

Alfa

AF:

0.00498

Hom.:

Bravo

AF:

0.00351

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00362

AC:

439

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00632

EpiControl

AF:

0.00628

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 10, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 26, 2014	Leu432Val in exon 08 of WFS1: This variant is not expected to have clinical sign ificance because it has been identified in 0.5% (43/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs35031397). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 06, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 10, 2015	- -

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	WFS1: PM5, BS2 -

Monogenic diabetes

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jul 22, 2016

ACMG Criteria:PP3, BP6 (ClinVar with 2 submitters calling this variant benign/Partners and GeneDx) Notes: no statistical difference between [deafness and DM] and 49 controls with this variant in Domenech et al 2002 EJHG (PMID:12107816). -

Meniere disease

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Center for Computational Biology & Bioinformatics, University of California, San Diego

Jun 03, 2024

- -

WFS1-Related Spectrum Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Wolfram syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Autosomal dominant nonsyndromic hearing loss 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;T

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.88

.;D

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.030

T;T

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-2.3

N;N

REVEL

Pathogenic

0.80

Sift

Uncertain

0.027

D;D

Sift4G

Uncertain

0.013

D;D

Polyphen

1.0

D;D

Vest4

0.78

MVP

0.95

ClinPred

0.040

GERP RS

4.7

Varity_R

0.15

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over